Directed ortho metalation (DoM) is an adaptation of
electrophilic aromatic substitution in which
electrophiles attach themselves exclusively to the
ortho- position of a
direct metalation group or DMG through the intermediary of an aryllithium compound. The DMG interacts with lithium through a
hetero atom
In chemistry, a heteroatom () is, strictly, any atom that is not carbon or hydrogen.
Organic chemistry
In practice, the term is usually used more specifically to indicate that non-carbon atoms have replaced carbon in the backbone of the molecul ...
. Examples of DMG's are the
methoxy group, a
tertiary amine group and an
amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
group.The compound can be produced by
directed lithiation of anisole.
The general principle is outlined in ''scheme 1''. An aromatic ring system with a DMG group 1 interacts with an
alkyllithium such as
''n''-butyllithium in its specific aggregation state (hence (R-Li)
n) to intermediate 2 since the hetero atom on the DMG is a
Lewis base
A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any sp ...
and lithium the
Lewis acid
A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any sp ...
. The very basic alkyllithium then
deprotonates
Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju.edu ...
the ring in the nearest ortho- position forming the aryllithium 3 all the while maintaining the acid-base interaction. An electrophile reacts in the next phase in an
electrophilic aromatic substitution with a strong preference for the lithium
ipso position replacing the lithium atom.
Ordinary electrophilic substitutions with an
activating group In electrophilic aromatic substitution reactions, existing substituent groups on the aromatic ring influence the overall reaction rate or have a directing effect on positional isomer of the products that are formed. An electron donating group (ED ...
show preference for both the ortho and para position, this reaction demonstrates increased
regioselectivity because the ortho position alone is targeted.
This reaction type was reported independently by
Henry Gilman
Henry Gilman (May 9, 1893 – November 7, 1986) was an American organic chemist known as the father of organometallic chemistry, the field within which his most notable work was done. He discovered the Gilman reagent, which bears his name.
Earl ...
and
Georg Wittig around 1940.
Examples
DOM has traditionally been applied to tertiary anilines and benzyl amines.
The method has also been applied to the synthesis of
enantiopure benzyl amines in ''scheme 3'', which involves ortho-lithiation of ''tert''-butyl phenyl sulfoxide. On approach to the lithium intermediate, the bulky
tosyl
In organic chemistry, a toluenesulfonyl group (tosyl group, abbreviated Ts or Tos) is a univalent functional group with the chemical formula –. It consists of a tolyl group, –, joined to a sulfonyl group, ––, with the open valence on s ...
group on the
imine electrophile is responsible for the
asymmetric induction
In stereochemistry, asymmetric induction (also enantioinduction) describes the preferential formation in a chemical reaction of one enantiomer or diastereoisomer over the other as a result of the influence of a chiral feature present in the sub ...
taking place.
In another application DOM is applied in placing a bulky
tert-butyl group in an ortho position (''scheme 4''). The lithiation is a
nucleophilic aromatic substitution and the subsequent reaction to the
sulfoxide
In organic chemistry, a sulfoxide, also called a sulphoxide, is an organosulfur compound containing a sulfinyl () functional group attached to two carbon atoms. It is a polar functional group. Sulfoxides are oxidized derivatives of sulfides. E ...
an
electrophilic aromatic substitution. In the final step
''tert''-butyllithium acts as a
nucleophile
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
in another nucleophilic aromatic substitution through an anionic intermediate.
D''o''M has also been applied combined with a
Suzuki reaction in a
one-pot synthesis
In chemistry a one-pot synthesis is a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one reactor. This is much desired by chemists because avoiding a lengthy separ ...
:
Thiophenol derivatives
DOM has also been used with
thiophenol
Thiophenol is an organosulfur compound with the formula C6H5SH, sometimes abbreviated as PhSH. This foul-smelling colorless liquid is the simplest aromatic thiol. The chemical structures of thiophenol and its derivatives are analogous to phenols ...
s to prepare compounds that are useful as hindered ligands.
Related reaction
Directed metallation is not limited to lithium intermediates or even to an ortho preference. In one study it is found that the reaction product of N,N-dimethylaniline with a complex of
TMEDA
Tetramethylethylenediamine (TMEDA or TEMED) is a chemical compound with the formula (CH3)2NCH2CH2N(CH3)2. This species is derived from ethylenediamine by replacement of the four amine hydrogens with four methyl groups. It is a colorless liquid, ...
, sodium salt of
TMP TMP can refer to any of the following:
Chemistry
* 2,2,6,6-Tetramethylpiperidine, an organic chemistry reagent
* Thymidine monophosphate, a nucleotide
* Trimethoprim, an antibiotic
* Trimethyl phosphate, a solvent
* Trimethylolpropane, a precurso ...
and
di-tert-butylzinc
Di-''tert''-butylzinc is a compound with the formula ZnC8H18. This compound is used as a ''meta'' activating reagent in the syntheses of ''N'',''N''-dimethyl-3-iodoaniline from ''N'',''N''-dimethylaniline.
Synthesis
Di-''tert''-butylzinc i ...
is a
meta
Meta (from the Greek μετά, '' meta'', meaning "after" or "beyond") is a prefix meaning "more comprehensive" or "transcending".
In modern nomenclature, ''meta''- can also serve as a prefix meaning self-referential, as a field of study or ende ...
zincated complex as a stable crystalline compound. This complex reacts with electrophilic
iodine
Iodine is a chemical element with the symbol I and atomic number 53. The heaviest of the stable halogens, it exists as a semi-lustrous, non-metallic solid at standard conditions that melts to form a deep violet liquid at , and boils to a vi ...
to N,N-dimethyl-3-iodoaniline:
[Solvent ]hexane
Hexane () is an organic compound, a straight-chain alkane with six carbon atoms and has the molecular formula C6H14.
It is a colorless liquid, odorless when pure, and with boiling points approximately . It is widely used as a cheap, relatively ...
reaction at room temperature
Colloquially, "room temperature" is a range of air temperatures that most people prefer for indoor settings. It feels comfortable to a person when they are wearing typical indoor clothing. Human comfort can extend beyond this range depending on ...
. Selected bond lengths in 2: Zn-C bond 203.5 pm in plane with aryl plane, Na-C bond 269 pm at 76° to aryl plane
References
{{reflist
Substitution reactions